This project is directed at understanding and characterizing the role of cytokines in the pathophysiology of infections, and evaluating their role in the treatment of these infectious diseases. We have used mycobacterial diseases as the system in which to examine the role of cytokines and cellular interactions, especially those of the monocyte/macrophage with the lymphocyte, in the generation of effective host defense. We hope to determine the underlying defects in patients with ineffective host defenses against mycobacteria (e.g., disseminated nontuberculous mycobacterial infections) and use these insights to develop novel immuno-adjuvant therapies. We have identified several patients with ineffective mycobacterial host defense as demonstrated by disseminated Mycobacterium avium infection in the absence of HIV infection. Most of these patients have low production of interferon gamma from peripheral blood mononuclear cells. We have extensively characterized one family with ineffective mycobacterial host defense as demonstrated by disseminated Mycobacterium avium infection in the absence of HIV infection. These familial patients have low production of interferon gamma, abnormal interleukin-12 regulation, and abnormal regulation of other cytokines. The determination of interleukin-12 deficiency in an infectious disease confirms the role of interleukin-12 in the control of intracellular infections in humans. We have successfully treated patients with nontuberculous mycobacterial infections with subcutaneous interferon gamma. Interferon gamma also has been used in the treatment of multiple-drug resistant tuberculosis.